Coverage Policy Manual
Policy #: 2015028
Category: Pharmacy
Initiated: September 2015
Last Review: October 2018
  Testosterone Replacement Therapy

Description:
Testosterone is produced in males primarily by the testes in response to stimuli from the hypothalamic and pituitary glands. Low testosterone is caused by deficient production of the hormone and is also known as androgen deficiency. Primary androgen deficiency results from failure of testosterone production at the testicular level in the presence of normal hypothalamic and pituitary function. Secondary androgen deficiency results from failure of production of androgen-stimulating hormones (luteinizing hormone, follicle-stimulating hormone) by the pituitary gland. It can be caused by dysfunction at the hypothalamic or pituitary level.
 
Hypogonadism is the clinical syndrome associated with androgen deficiency. The signs and symptoms of hypogonadism depend on the age of onset. In prepubertal males, the hallmark of androgen deficiency is the failure to develop secondary male sex characteristics. In adults, the signs and symptoms are nonspecific, with the most specific symptoms related to sexual functioning such as decreased libido and erectile dysfunction. Symptoms are dependent on age, severity of androgen deficiency, duration of androgen deficiency, individual sensitivity to androgen, and comorbid illness (Bhasin, 2010). Symptoms and signs other than sexual dysfunction include loss of body hair, hot flushes or sweats, decreased energy, depression, sleep disturbance, reduced muscle mass and strength, and/or increased body fat. These can all occur in the absence of androgen deficiency and, therefore the diagnosis of hypogonadism can be challenging. A 2014 systematic review of studies that reported on risk factors, comorbidities, and consequences of male hypogonadism identified multiple comorbid conditions that were consistently risk factors for hypogonadism, including advanced age, obesity, a diagnosis of metabolic syndrome, and poor general health status (Zarotsky, 2014).  Multiple other conditions, including diabetes, coronary heart disease, hypertension, stroke, and peripheral artery disease were correlated with the presence of hypogonadism, although were not identified as risk factors.
 
Testosterone levels decrease with age beginning in the fourth or fifth decade, and this decrease is sometimes referred to as male “andropause.” In the European Male Aging Study of 3220 men, there was a decline in serum testosterone levels of 0.4% per year between the ages of 40 and 70 (Wu, 2008).  Since this decline is gradual and modest, the clinical impact is uncertain. While there are also parallel decreases in androgen-dependent factors with age, such as sexual function, lean body mass, and BMD, the degree to which these changes are due to decreasing testosterone has not been determined with certainty. Because of the decline in testosterone levels with age, more elderly males will have low levels compared with younger men. Using a cutoff of 325 ng/dL as the lower limit of normal testosterone levels, one prospective cohort study of 890 men estimated that the rate of low testosterone is 20% for men in their 60s; 30% for men in their 70s; and 50% for men in their 80s (Travison, 2007). In this study, there were other factors that were associated with decreased testosterone, such as obesity and severe emotional stress. A much lower percentage of men have a combination of low testosterone levels and definite symptoms of hypogonadism. In the European Male Aging Study, this was estimated to be present in 2.3% of men when using a cutoff of at least 3 symptoms potentially related to androgen deficiency.
 
Another factor that makes the diagnosis of hypogonadism challenging is the measurement of testosterone levels. Testosterone levels fluctuate substantially due to a variety of factors. There is a diurnal variation, which is more pronounced in younger men, with peak levels occurring in the early morning. This makes the timing of measurement important and requires repeated measurement before making a determination that testosterone is consistently low. Also, there is a wide range of levels seen in healthy men, and assigning the proper age-appropriate cutoff is controversial. Some men exhibit clear symptoms of hypogonadism with testosterone levels that are in the low normal range, while other men with low levels do not experience any symptoms.
 
Testosterone Replacement
There are numerous different Food and Drug Administration (FDA)‒approved formulations of testosterone that are available for replacement therapy. For most delivery preparations, FDA approval was granted on the ability to increase levels to the normal range and not on demonstration of beneficial clinical outcomes (Cunningham, 2011).
 
· Oral testosterone: The most common forms of oral testosterone in clinical use are testosterone enanthate and testosterone cypionate, which are generally dosed twice daily. Oral testosterone is readily absorbed from the intestine and is rapidly metabolized by the liver. The rapid metabolism in the liver limits its clinical utility, as it is difficult to maintain steady serum levels. In addition, the first pass through the liver may increase the probability of liver toxicity.
· Intramuscular testosterone: Testosterone undecanoate is an intramuscular (IM) depot preparation of testosterone that is slowly absorbed into the circulation. It is administered by deep IM injection every 10 to 14 weeks, and thus has the advantage of infrequent dosing. Disadvantages of this preparation include the IM injection route, which can be painful, and inconsistent rates of absorption. Inconsistent absorption can lead to fluctuating testosterone levels, with associated fluctuations in clinical symptoms.
· Topical patch: Topical testosterone patches are available and can be applied to nongenital skin areas. Patches are generally dosed once per day and result in stable testosterone levels over time. A limiting factor in the use of patches is the development of skin irritation at the patch site in a high percentage of users.
· Topical gel: A number of topical testosterone gel preparations are commercially available. They range in strength from 1% to 2% and result in stable serum levels. The gel is applied daily on nongenital skin areas. Precautions need to be taken to avoid transmission of the drug to others by direct contact, therefore it is recommended that the gel be placed on covered skin and that handwashing is performed after application.
· Buccal tablets: Buccal tablets are commercially available and are applied twice per day to the gums over the upper incisors. Testosterone is absorbed through the buccal mucosa into the systemic circulation.
· Subcutaneous pellets: Another depot formulation of testosterone is a subcutaneous testosterone tablet. These are placed subcutaneously in the buttocks, abdominal wall, or thigh under local anesthesia. They are replaced every 3 to 6 months. Limitations include the need for a minor surgical procedures, and local reactions at the implantation site, such as infections or fibrosis.
*Note: The use of subcutaneous hormone pellet implantation is addressed in a separate policy #2009047.
 
Contraindications to Testosterone Therapy
Contraindications to Testosterone Therapy include the following as noted by the Endocrine Society Guidelines for Testosterone Therapy 2018: in men planning fertility in the near term or in men with breast or prostate cancer, a palpable prostate nodule or induration, a prostate-specific antigen level >4 ng/mL, a prostate-specific antigen level >3 ng/mL combined with a high risk of prostate cancer (without further urological evaluation), elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia (Bhasin et al, 2018)
 
Regulatory Status
There are numerous preparations of testosterone that have received FDA approval for use in testosterone replacement therapy. These include IM, oral, topical, subcutaneous and buccal preparations. In January 2014, FDA announced its plan to investigate the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products based on increased risks reported in several studies (FDA, 2014). In September 2014, at a meeting of the FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee, the committee reported that FDA had not concluded that FDA-approved testosterone treatment increases the risk of stroke, heart attack, and death. However, the Advisory Committee voted in favor of changing the current FDA labeling for indications for testosterone therapies, with committee members stating that the indication for testosterone therapy should be limited to men with classical hypogonadism (FDA, 2014).
 
Related policies:  #2009047 Hormone Pellet Implantation for Hormone Replacement Therapy

Policy/
Coverage:
Effective October 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testosterone replacement therapy when administered according to the dosing guidelines below meets member benefit certificate primary coverage criteria under at least one of the following conditions:
 
1) An established diagnosis of hypogonadism with androgen deficiency that includes:
 
    • Persistently low testosterone levels as evidenced by 2 early morning fasting serum total testosterone levels that are below 300 ng/dL on both days, AND
 
    • At least 2 of the following symptoms:
 
        • incomplete or delayed sexual development;
        • loss of axillar and/or pubic body hair;
        • very small (<6ml) or shrinking testes;  
        • decreased libido;
        • decreased spontaneous erections;
        • breast discomfort and gynecomastia;
        • eunuchoidal body proportions;
        • infertility due to low sperm count;
        • height loss due to vertebral fractures, low trauma fractures, low bone density;  
        • hot flushes/sweats;
 
 
OR
 
2) HIV-infected men with low testosterone levels and weight loss;
 
OR
 
3) Men on chronic steroid treatment with low testosterone levels.
 
  
*Dosing Guidelines
        • T enanthate or cypionate: 150–200 mg intramuscularly every 2 weeks, or 75 mg intramuscularly weekly,
        • T transdermal gels: 1% (50-100 mg daily), 1.62% (20.25-81mg daily), or 2% (40-70 mg daily)
        • T Axillary solution:  60 mg applied in the axillae daily.
        • Transdermal T patch : One or two patches, designed to nominally deliver 2–4 mg of T during 24 h applied every day on nonpressure areas
        • Buccal, bioadhesive T tablets: 30-mg controlled release, bioadhesive tablets twice daily
        • T pellets:  Pellets containing 600–1200 mg T implanted SC; the number of pellets and the regimen may vary with formulation
        • Injectable long-acting T undecanoate in oil: 750 mg IM, followed by 750 mg at 4 wk, and 750 mg every 10 wk
        • Nasal T gel:  11 mg two or three times daily
 
*Dosing guidelines per 2018 Endocrine Society Clinical Practice Guidelines (Bhasin et al, 2018)
 
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testosterone replacement therapy does not meet member benefit certificate primary coverage criteria in all other situations in which the above criteria are not met, including but not limited to older men (65 years or older) with low testosterone levels in the absence of clinical signs and symptoms of hypogonadism.
 
For members with contracts without primary coverage criteria, testosterone replacement therapy is considered investigational in all other situations in which the above criteria are not met, including but not limited to older men (65 years or older) with low testosterone levels in the absence of clinical signs and symptoms of hypogonadism.
 
Effective September 2017 to September 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testosterone replacement therapy when administered according to the dosing guidelines below meets member benefit certificate primary coverage criteria under at least one of the following conditions:
 
1) An established diagnosis of hypogonadism with androgen deficiency that includes:
    • Persistently low testosterone levels as evidenced by serum levels that are below the lower limit of normal (as specified by the lab assay) on at least 2 occasions when measured early in the morning, AND
    • At least 2 symptoms of hypogonadism including at least 1 of the following  “more specific” symptoms:
        • incomplete or delayed sexual development;
        • decreased libido;
        • decreased spontaneous erections;
        • breast discomfort and gynecomastia;
        •  loss of axillar and/or pubic body hair, very small (<5ml) or shrinking testes;  
        • infertility due to low sperm count;
        • height loss due to vertebral fractures, low trauma fractures, low bone density;  
        • hot flushes/sweats.; OR
 
2) HIV-infected men with low testosterone levels and weight loss; OR
 
3) Men on chronic steroid treatment with low testosterone levels.
  
*Dosing Guidelines:
•75 to 100 mg of testosterone enanthate or cypionate intramuscularly weekly, or 150–200 mg intramuscularly every 2 weeks (a maximum of 400 mg every 4 weeks)
•One or two 5-mg testosterone patches nightly
•5 to 10 g of 1% testosterone gel daily
•30 mg of a bioadhesive buccal testosterone tablet every 12 hours
•Testosterone pellets implanted subcutaneously every 3 to 6 months (the dose and regimen vary by formulation)
 
*Dosing guidelines per 2010 Endocrine Society Clinical Practice Guidelines (Bhasin, 2010)
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testosterone replacement therapy does not meet member benefit certificate primary coverage criteria in all other situations in which the above criteria are not met, including but not limited to older men with low testosterone levels in the absence of clinical signs and symptoms of hypogonadism.
 
For members with contracts without primary coverage criteria, testosterone replacement therapy is considered investigational in all other situations in which the above criteria are not met, including but not limited to older men with low testosterone levels in the absence of clinical signs and symptoms of hypogonadism.
 
Effective Prior to September 2017
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testosterone replacement therapy meets member benefit certificate primary coverage criteria under at least one of the following conditions:
 
· An established diagnosis of hypogonadism with androgen deficiency that includes:
o Persistently low testosterone levels as evidenced by serum levels that are below the lower limit of normal (as specified by the lab assay) on at least 2 occasions when measured early in the morning, AND
o At least 2 symptoms of hypogonadism including at least 1 of the following  “more specific” symptoms:
        • incomplete or delayed sexual development;
        • decreased libido;
        • decreased spontaneous erections;
        • breast discomfort and gynecomastia;
        •  loss of axillar and/or pubic body hair, very small (<5ml) or shrinking testes;
        • infertility due to low sperm count;
        • height loss due to vertebral fractures, low trauma fractures, low bone density;
        • hot flushes/sweats.; OR
· HIV-infected men with low testosterone levels and weight loss; OR
· Men on chronic steroid treatment with low testosterone levels.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testosterone replacement therapy does not meet member benefit certificate primary coverage criteria in all other situations in which the above criteria are not met, including but not limited to older men with low testosterone levels in the absence of clinical signs and symptoms of hypogonadism.
 
For members with contracts without primary coverage criteria, testosterone replacement therapy is considered investigational in all other situations in which the above criteria are not met, including but not limited to older men with low testosterone levels in the absence of clinical signs and symptoms of hypogonadism.

Rationale:
Assessment of efficacy for therapeutic intervention involves a determination of whether the intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes, but are prone to biases such as noncomparability of treatment groups, the placebo effect, and variable natural history of the condition.
 
There is a large body of literature that evaluates the efficacy of testosterone replacement therapy. This body of evidence is primarily characterized by small- to medium-sized trials of short duration. There is a high degree of variability in the patient populations, dose and delivery method for testosterone replacement, and outcomes measured. There are also numerous systematic reviews of the available evidence. The following evidence review will focus on the impact of testosterone on specific symptoms for adults with androgen deficiency and clinical symptoms of hypogonadism, and on the benefit for specific subpopulations. Emphasis is on the available systematic reviews and larger individual RCTs.
 
Adults With Androgen Deficiency and Clinical Symptoms
Sexual Dysfunction
There are a large number of RCTs that have evaluated the effect of testosterone replacement on sexual function in men with hypogonadism and low or low-normal testosterone levels. A systematic review of 17 RCTs with placebo control was published in 2007 by Bolona et al (Bolona, 2007). Most of the included trials were small, with a combined enrollment of 862 patients. The methodologic quality of these trials was not high, with most trials not reporting methods taken to limit bias. There was also reporting bias noted, with incomplete data on the range of measured outcomes, and high dropout rates in many of the studies. Combined results indicated a strong effect for an increase in libido in men treated with testosterone. On subgroup analysis, the impact of testosterone replacement was substantially greater for studies that enrolled men with low mean testosterone levels compared with studies that enrolled men with low-normal levels. On combined analysis, there was also a positive impact on erectile dysfunction, but the strength of this effect was moderate and not as consistently reported as for changes in libido. There was no significant effect on overall sexual satisfaction in combined analysis. The authors also reported large variability in the results of the studies and wide confidence intervals around the combined results for each outcome. Subgroup analysis was unable to provide adequate explanations for the variability in study results.
 
Another systematic review reported specifically on the impact of testosterone replacement for erectile Dysfunction (Jain, 2000). This review included 16 randomized and nonrandomized studies and limited combined analysis to studies that reported a response rate by predefined criteria. Combined analysis showed that 57% of treated men had a positive response to testosterone. The response rate was higher for men with primary hypogonadism (64%) compared with men with secondary hypogonadism (44%, p<0.001). There was also a higher response rate for patients treated with transdermal preparations (80.9%) compared with patients treated with IM or oral preparations (51.3% and 53.25%, respectively, p<0.001). Since publication of the systematic reviews, Pexman-Fieth et al reported improvements in erectile function and quality of life among 799 men treated with transdermal testosterone over a 6-month period (Pexman-Fieth, 2014).
 
Body Composition, Muscle Strength, and Physical Function
Bhasin et al performed a meta-analysis of 10 trials that evaluated the effect of testosterone replacement on body composition (Bhasin, 2006). They reported a mean increase of 1.1 kg in total body mass and a mean increase of 1.7 kg (95% confidence interval [CI], 1.52 to 1.96) in lean body mass. There was a correlation of the increase in lean body mass with the dose of testosterone given, and with circulating testosterone levels. The effects were less consistent for muscle strength and muscle function. The authors reported an increase in leg strength, but no impact on muscle endurance or muscle tension.
 
Bone Mineral Density
In a meta-analysis published in 2006, Tracz et al evaluated the impact of testosterone replacement on bone mineral density (BMD) (Tracz, 2006). The trials included in this review were small, with a total population of 365 patients, and only1 trial followed patients for more than 1 year. Testosterone given by the IM route led to an 8% increase (95% CI, 4% to 13%) in density of the lumbar spine, although transdermal treatment did not lead to any significant increases. There was also a 4% increase in density at the femoral neck (95% CI, 2% to 9%).
 
Other Outcomes
Evidence on the impact of testosterone replacement on other outcomes, such as depression, quality of life and cognition, is limited.
 
A few small studies have reported benefit in patients with low testosterone and depression. Amiaz et al reported results of an RCT of 100 men with depression treated with selective serotonin reuptake inhibitors and low or low-normal testosterone. After 6 weeks of treatment, there were significant improvements for patients treated with testosterone compared with placebo on the International Index of Erectile Function Scale. The greatest impact was on the subscale for ejaculatory ability. In 2 studies of men with dysthymia, with enrollments of 33 and 23 total patients, treatment with testosterone lead to greater improvements on the Hamilton Rating Scale for depression and a higher remission rate compared with placebo (Shores, 2009; Seidman, 2009). Borst et al reported results from a small prospective RCT assessing the cognitive benefit of testosterone, with or without the 5a-reductase inhibitor finasteride, in men aged 60 or older with low serum testosterone and no evidence of cognitive impairment (Borst, 2014). Patients were randomized to either placebo, testosterone-enanthate with placebo, finasteride with testosterone vehicle (placebo), or testosterone with finasteride. Compared with placebo, testosterone was associated with a small decrease in depressive symptoms as measured by the 15-point Geriatric Depression Scale (absolute score reduction, -0.74 points; 95% CI, -1.41 to -0.06; p=0.04). Testosterone was also associated with a moderate increase in visuospatial memory.
 
Androgen Deficiency in Patients With HIV Infection
There is a high prevalence of androgen deficiency in patients with HIV infection who are on antiviral treatment, with up to 25% of this population having low testosterone levels. Men with low levels of testosterone have worse outcomes of HIV disease, including increased progression of disease, loss of muscle mass, and declines in physical functioning (Bhasin, 2010).
 
A systematic review of testosterone replacement in HIV-infected men with weight loss was performed by Bhasin et al (bhasin, 2006). These authors identified 8 trials of testosterone replacement in HIV-infected patients with weight loss. The trials were of variable quality and heterogeneous in their methodology. Combined analysis of changes in body weight, fat free mass, and lean body mass was performed. There was an estimated increase of 1.1 kg in body weight (95% CI, 0.2 to 2.0), 1.4 kg in fat-free mass (95% CI, 0.7 to 2.1), and 1.3 kg in lean body mass (95% CI, 0.4 to 2.2) associated with testosterone replacement. This systematic review also reviewed the outcomes of muscle strength and depression. Three trials reported on changes in muscle strength, with 2 of the 3 reporting significant improvements with testosterone. Four trials reported on changes in depression, with combined analysis showing a modest increase in depression scores for testosterone-treated patients. There were no significant changes in parameters of HIV infection, such as T lymphocyte or viral load for patients treated with testosterone.
 
Androgen Deficiency in Patients on Chronic Steroid Treatment
Patients who are treated with chronic steroid therapy have lower levels of testosterone compared with age-matched patients who are not on steroids. This effect is thought to be due to direct suppression of the hypothalamic-pituitary axis by steroids, as well as a direct suppression of testosterone production in the testes. This hormonal suppression contributes to the increase in abdominal fat and decrease in BMD seen in patients treated chronically with steroids.
 
The systematic review by Bhasin et al identified 2 placebo-controlled RCTs of testosterone replacement in patients on chronic steroid treatment for asthma or chronic obstructive pulmonary disease (Bhasin, 2006). The trials were limited by small sample size and short duration of follow-up. Combined analysis of the 2 trials showed a significant increase in lean body mass of 2.3 kg (95% CI, 2.0 to 3.6) and a significant decrease in fat mass of 3.1 kg (95% CI, -2.8 to -3.5). There was also a significant improvement in lumbar bone density of 4% (95% CI, 2% to 7%), although there was no significant improvement found in BMD of the femoral neck.
 
Androgen Deficiency in Patients with Type II Diabetes
Cai et al reported results of a systematic review and meta-analysis of RCTs that evaluated the effect of testosterone therapy on metabolic parameters in patients with type 2 diabetes and hypogonadism (Cai, 2014). Five RCTs, including 351 subjects were identified that met eligibility criteria, 3 of which were double-blind, placebo-controlled trials and 2 of which were open-label and single-blind, no treatment controlled trials. In pooled analysis, testosterone was associated with reduced fasting plasma glucose levels (mean difference [MD], -1.10; 95% CI, -1.88 to -0.31), fasting insulin levels (MD, -2.73; 95% CI, -3.63 to -1.84), hemoglobin A1C (HbA1c; MD, -0.87; 95% CI, -1.32 to -0.42), and triglyceride levels (MD, -0.35; 95% CI, - 0.62 to -0.07). The authors note that the studies analyzed were limited by relatively few participants and limited discussion of methods.
 
One of the larger RCTs included in the Cai et al meta-analysis enrolled 220 patients with type 2 diabetes and/or metabolic syndrome and hypogonadism (Jones, 2011). Treatment in the testosterone group was with 60 mg of transdermal testosterone daily. The primary outcome was the change in insulin resistance, as measured by the homeostasis model of insulin resistance (HOMA-IR), and secondary outcomes were changes in body composition, glycemic control, lipids, and sexual dysfunction. There was a 16% reduction in the HOMA-IR at 6-month follow-up (p<0.02), and this difference persisted at 12-month follow-up. Other outcomes were reported at 6-month follow-up. There were statistically significant improvements for the overall group in the International Index of Erectile Function Score for the testosterone group, but no significant improvement in the HgA1C or fasting glucose levels. There were no differences for the overall group on measures of body composition or lipid levels. On subgroup analysis, there was an improvement for patients with metabolic syndrome on the mean low-density lipoprotein level.
 
In an RCT not included in the 2014 Cai et al meta-analysis, Hackett et al randomized 211 patients with type 2 diabetes and hypogonadism to received parenteral testosterone (1000 mg testosterone undecanoate at week 0, week 6, and week 18) or placebo and followed for 30 weeks (Hackett, 2014). For the study’s primary outcome, change in HbA1c level, testosterone treatment was associated with a significant reduction in HbA1c at 6 weeks of therapy (from 7.74 to 7.50%). At 18 weeks of therapy, with an MD between treatment and control group, after adjustment for covariates, of -0.20 (95% CI, -0.34 to -0.05; p=0.007). There was significant reduction in waist circumference, weight, and BMI in men without depression. No major AEs were reported.
 
Older Men With Low Testosterone Levels Without Definite Hypogonadism
There have been a few RCTs that have evaluated the impact of testosterone replacement on elderly males with low testosterone levels, without definite evidence of hypogonadism. Most of these have been small and included only a limited range of outcomes. Some of the representative RCTs are discussed next, including 2 of the larger trials (Emmelot-Vonk, 2008; Legros, 2009).
 
A trial by Emmelot-Vonk et al was published in 2008 that enrolled 237 men between the ages of 60 to 80 years who had a low testosterone level but were otherwise healthy (Emmelot-Vonk, 2008). Patients were randomized to 80 mg of oral testosterone or placebo and followed for 6 months. A range of outcome measures were reported, including functional mobility, body composition, muscle strength, cognitive function, BMD, metabolic parameters, and quality of life. Safety outcomes were also included; prostate-specific antigen (PSA), prostate volume, renal function, liver function, and hematocrit levels.
 
For most of the outcome measures, there was no improvement in the testosterone group compared with placebo. There was an increase in lean body mass and a decrease in the percent body fat. However, these changes were not accompanied by improvements in functional capacity or muscle strength. There were no significant changes in cognitive function, BMD, or quality of life. There was a trend toward worsening metabolic profile, with 47.8% of men in the testosterone group meeting the definition for metabolic syndrome at the end of the study compared with 35.5% of men in the placebo group (p=0.07). There was a significant but small increase in hematocrit from men in the testosterone group and an increase in creatinine that was of borderline significance. Otherwise there were no group differences in the safety outcomes.
 
Another larger trial was a multicenter RCT from Europe that enrolled 322 patients who were 50 years or older, with mild-to-moderate symptoms of hypogonadism, and a low testosterone level (Legros, 2009). Patients were randomized to 80 mg, 160 mg, or 240 mg of testosterone daily or placebo, and the primary outcome was the change in the Aging Males Symptom (AMS) measure at 6 months. There were no statistically significant differences on the total AMS score between groups at 6 months, although the scores in the testosterone group showed a greater numerical improvement. There was a statistically significant difference in the AMS sexual domain subscore for the 160-mg testosterone group, but not for the 80- or 240-mg group. There were no statistically significant differences in AEs between groups, including the change in PSA level.
 
Several other smaller RCTs have been published, ranging from 13 to 131 patients (Kenny, 2010; Kenny, 2010; Snyder, 1999; Sih, 1997; Tenover, 1992). The most consistent finding reported in these studies was an increase in lean body mass (4 studies) and a decrease in body fat (3 studies). The impact on strength was mixed, with 2 studies reporting an improvement in the testosterone group and 2 studies reporting no difference between groups. An increased in hemoglobin and/or hematocrit was reported in one of the studies, and an increase in BMD also reported in one of the studies. None of these RCTs reported on functional status, quality of life, or sexual performance.
 
AEs of Testosterone Therapy
There is a long list of potential adverse effects that could occur with testosterone replacement, as Follows (Cunningham, 2011):
 
· Prostate-related events, including development or worsening of prostate cancer, prostatic hypertrophy, increases in PSA levels, and symptoms of prostatism.
· Cardiovascular events
· Adverse changes in lipid profile
· Erythrocytosis and increases in hematocrit
· Precipitation or worsening of sleep apnea
· Liver toxicity
· Suppression of spermatogenesis
· Acne
· Worsening of male pattern baldness
· Gynecomastia
 
The clinical significance of many of these potential AEs is unclear. Several meta-analyses of Aes that are expected to be more common have been published. This review of AEs will include both randomized and nonrandomized studies, with emphasis on systematic reviews and meta-analyses of the available studies.
 
Fernandez-Balsells et al published a meta-analysis of randomized and nonrandomized comparative studies in 2010 (Fernandez-Balsells, 2010). This review included 51 studies and examined the outcomes of mortality, cardiovascular events, cardiovascular risk factors, prostate events, and erythrocytosis. Patients treated with testosterone had increased hematocrit (weighted mean difference, 3.2%; 95% CI, 1.4% to 5.0%), and decreased high-density lipoprotein level (weighted mean difference, 0.5 mg/dL; 95% CI, 0.13 to 0.85). There were no significant differences reported in mortality, cardiovascular events, or prostate-related events. Calof et al performed a meta-analysis of placebo-controlled RCTs published in 2005 (Calof, 2005).Nineteen studies were included that reported on 1084 patients, and the outcomes of mortality, prostate-related events, changes in hematocrit, and sleep apnea were examined. Patients treated with testosterone had a higher overall rate of prostate-related events (odds ratio [OR], 1.78; 95% CI, 1.0 to 2.9), but no significant increase in prostate cancer. Patients treated with testosterone were also more likely to have a hematocrit greater than 50% (OR=3.7; 95% CI, 1.8 to 7.5). There were no significant differences in mortality, cardiovascular events, or sleep apnea. In another meta-analysis of placebo-controlled RCTs, Haddad et al examined the rates of adverse cardiovascular events and changes in cardiovascular risk factors.30 This review included 30 trials that reported on 1642 men. Total adverse cardiovascular events were numerically more frequent in testosterone-treated patients, but the difference did not reach statistical significance (OR=1.8; 95% CI, 0.8 to 4.2). There were small changes in blood
pressure, lipid levels, and glucose, but none of these changes reached statistical significance.
 
Several meta-analyses have specifically evaluated the relationship between testosterone and prostate-related events. In 2014, Cui et al conducted a meta-analysis of RCTs, which reported the effect of testosterone replacement on prostate growth (Cui, 2013). Sixteen RCTs comparing testosterone replacement with placebo including 1030 patients were included, 7 of which were short term (<12 months) and 9 that were long term (12-36 months). Seven studies evaluated transdermally administered testosterone, while 6 evaluated injected testosterone and 3 evaluated orally administered testosterone. In the short term, transdermal, but not orally administered or injected testosterone administration, was significantly associated with changes in PSA levels (standardized mean difference [SMD], 0.30; 95% CI, 0.07 to 0.54; p=0.002). However, there was no significant association between testosterone administration and PSA levels over the longer term. Testosterone administration by any method was not associated with significant differences in International Prostate Symptom Score, prostate volume, or maximum urine flow rate. In a separate publication, Cui et al conducted a meta-analysis of RCTs, which reported the effect of testosterone replacement therapy on prostate cancer risk (Cui, 2014). This analysis included 22 RCTs including a total of 2351 patients, 11 of which reported short-term (<12 months) outcomes and 11 of which reported long-term (12-36 months) outcomes. Five studies evaluated injectable testosterone, 1 evaluated oral testosterone, and 5 evaluated transdermal testosterone over the short term; there was no significant association between any administration method and prostate cancer, prostate biopsy, or prostate nodules. However, for the studies evaluating transdermal testosterone, there was a significant association between testosterone treatment and change in PSA level (SMD=0.33; 95% CI, 0.21 to 0.45; p<0.000). There was no association between testosterone therapy and abnormal PSA levels. For long-term administration, 3 studies evaluated injectable testosterone, 2 evaluated oral testosterone, and 6 evaluated transdermally-administered testosterone. There was no significant association between testosterone administration by any method and prostate cancer, prostate biopsy, or prostate nodules. No significant association was found between testosterone administration over the long term and change in PSA level.
 
Several cohort studies published since the systematic reviews previously outlined reported no association between testosterone replacement therapy and lower urinary tract symptoms (Francomano, 2014; Pearl, 2013).
 
Since publication of the meta-analyses evaluating cardiovascular risk and testosterone replacement, at least 2 additional studies have reported on adverse cardiovascular effects associated with testosterone replacement. The Testosterone in Older Men with Mobility Limitations trial was a placebo controlled trial intended to evaluate the effect of testosterone replacement on strength and functional status in 250 men older than 65 years with low testosterone levels (Basaria, 2010). The study was terminated early due to excess adverse cardiovascular events in the testosterone group after enrollment of 209 men, 129 of whom had completed the 6-month treatment period. A broad definition of cardiovascular events was used that included cardiac death, myocardial infarction (MI), revascularization procedures, stroke, elevated blood pressure, abnormal results on stress testing, arrhythmias, exacerbations of heart failure, syncope, and peripheral edema. The hazard ratio for total adverse cardiovascular events in the testosterone group was 2.4 (p=0.05). This increase in AEs persisted when 2 different definitions for cardiovascular events were tested.
 
A large retrospective comparative cohort study evaluated the risk of cardiovascular events in patients treated with testosterone replacement therapy (Vigen, 2013). This study used data from the Veterans Administration Clinical Assessment Reporting and Tracking Program to identify all male patients who had both undergone coronary angiography and had a total testosterone level checked between 2005 and 2011. There were 8709 patients with a low testosterone level, defined as less than 300 ng/dL. The population had high levels of comorbidity, with 80% of patients having coronary artery disease, 50% diabetes, and 20% prior MI. There were 1223 patients treated with testosterone and 7486 who were not treated. After a mean follow-up of 27.5 months, the primary outcome of all-cause mortality, MI, or stroke was more frequent in the group treated with testosterone (hazard ratio [HR], 1.29; 95% CI, 1.04 to 1.58; p=0.02).
 
Finkle et al conducted a large retrospective cohort study using administrative claims data to assess the relationship between testosterone therapy and non-fatal MI (Finkle, 2014). The authors generated a cohort of 55,593 men who filled a first prescription for one of several testosterone prescriptions between 2008 and 2010 from the Truven Health MarketScan® Commercial Claims and Encounters Database, which includes diagnoses, procedures, and prescriptions for all enrollees of contributing health plans. Testosterone recipients were compared with a population of men who filled a first prescription for a phosphodiesterase type 5 inhibitor (PDE5I; sildenafil or tadalafil; N=167,279) during the same time period. For testosterone recipients, the rate ratio (RR) of MI in the post-testosterone period compared with the pre-testosterone period was 1.36 (95% CI, 1.03 to 1.81). Compared with subjects in the PDE5I group, the ratio of the rate ratio for MI risk for testosterone recipients was 1.90 (95% CI, 1.04 to 3.49). After stratifying by age, for testosterone recipients younger than age 55 years, the RR for MI in the post-testosterone period was 0.95 (95% CI, 0.54 to 1.67), while for testosterone recipients aged 75 and older, the RR for MI in the post-testosterone period was 3.43 (95% CI, 1.54 to 7.56; P for trend 0.03). No similar trend was seen for PDE5I recipients. Although this study suggests an association between testosterone use and nonfatal MI, it is limited by its retrospective design and the potential for confounding by measured and unmeasured variables.
 
Another large retrospective cohort study that used administrative claims data from Medicare assessed the relationship between IM testosterone and MI risk (Baillargeon, 2014). The study included 6355 Medicare beneficiaries who received at least 1 testosterone injection between 1997 and 2005 and who were matched in a 1:3 ratio to 19,065 testosterone nonusers based on a composite MI prognostic score. After adjustment for demographic and clinical covariates, testosterone therapy was not associated with an increased risk of MI (adjusted HR=0.84; 95% CI, 0.69 to 1.01). Testosterone therapy was associated with a reduced risk of MI in men with an MI prognostic score in the highest quartile (HR=0.69; 95% CI, 0.53 to 0.92), while men in the lower three quartiles showed no difference in MI risk with testosterone therapy.
 
In another large retrospective population-based cohort study which used linked data from Medicare claims and the Surveillance, Epidemiology, and End Results, Kaplan et al evaluated the association between testosterone therapy after prostate cancer treatment and prostate cancer-specific mortality (Kaplan, 2014). Of 149,354 men diagnosed with prostate cancer between 1992 and 2007, 1181 (0.79%) received testosterone replacement therapy after their cancer diagnosis. After propensity-score adjustment for potential confounders, patients who did not received testosterone replacement therapy had higher overall and cancer-specific mortality compared with those who received testosterone replacement therapy (6.9 vs 5.4 and 1.6 vs 0.9 events per 100 person-years, respectively; p<0.001). The authors state that the reason for the lower mortality in the testosterone replacement therapy group is unclear.
 
Ongoing and Unpublished Clinical Trials
There are a large number of ongoing trials of testosterone replacement therapy. A search of ClinicalTrials.gov in October 2014 using the keywords testosterone replacement, and restricted to intervention trials, returned 122 ongoing trials. Most of these are RCTs in various stages of development. They cover a wide range of potential patient populations, from elderly men with low testosterone levels to more specific populations such as men with prostate cancer. They also cover a wide range of different types of testosterone replacement formulations.
 
Summary of Evidence
For men with low testosterone levels and sexual dysfunction, the evidence is fairly consistent in demonstrating a beneficial effect on increased libido. Other sexual symptoms such as erectile dysfunction are also likely to be improved, but the evidence is less strong. For nonsexual symptoms, there is evidence that lean body mass is increased, body fat is decreased, and bone mineral density is increased with testosterone therapy. However, the impact of these changes on functional status and fractures is less clear. For outcomes such as decreased energy, depression, quality of life and cognition, the evidence is limited and not consistent in reporting benefits of replacement therapy. In patients with HIV infection and weight loss, and in patients on chronic steroid therapy, a limited number of trials report improvements in body weight, lean body mass, and a decrease in body fat.
 
The adverse effect profile of testosterone therapy is not well-defined, but there are concerns for increased adverse prostate-related outcomes and cardiovascular outcomes. While some studies report an association between testosterone replacement and either prostate-related events or cardiovascular events, these findings are not consistent and a definite link has not been established. This uncertainty in the adverse event profile creates challenges in determining the risk/benefit ratio of treatment. Based on the available evidence, testosterone replacement therapy may be considered medically necessary in men with low testosterone levels and definite clinical evidence of hypogonadism. It may also be considered medically necessary for patients on chronic steroids who have low testosterone levels, and the HIV-infected patients with weight loss and low testosterone levels. In all other situations, testosterone replacement therapy is considered investigational, because the benefit is uncertain.
 
Practice Guidelines and Position Statements
The Endocrine Society published clinical practice guidelines on Testosterone Therapy in Men with Androgen Deficiency in 2006, (Bhasin, 2006) with an update published in 2010 (Bhasin, 2010). The 2010 guidelines included the following statements on the diagnosis of androgen deficiency and therapy with testosterone replacement:
    • We recommend making the diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. (Strong recommendation; very low quality of evidence)
    • We recommend testosterone therapy for symptomatic men with classical androgen deficiency syndromes aimed at inducing and maintaining secondary sex characteristics and at improving their sexual function, sense of well-being, and bone mineral density (Strong recommendation; low quality evidence
    • We recommend against testosterone therapy in patients with breast or prostate cancer. (Strong recommendation; quality of evidence very low for breast cancer, low for prostate cancer)
    •  We recommend that clinicians assess prostate cancer risk in men being considered for testosterone therapy. (Strong recommendation; very low quality of evidence)
    •  We suggest initiating testosterone therapy with any of the following regimens, chosen on the basis of the patient’s preference, consideration of pharmacokinetics, treatment burden, and cost.(Weak recommendation; strength of evidence low)
      • 75 to 100 mg of testosterone enanthate or cypionate administered IM [intramuscularly]
weekly, or 150 to 200 mg administered every 2 weeks.
      • One or two 5 mg non-genital, testosterone patches applied nightly over the skin of the back,
thigh, or upper arms, away from pressure areas.
      • 5 to 10 g of a 1% testosterone gel applied daily over a covered area of non-genital skin.
      • 30 mg of a bioadhesive buccal testosterone tablet applied to buccal mucosa every 12 hours.
      • Testosterone pellets implanted SC [subcutaneous] at intervals of 3 to 6 months; the dose and
regimen vary with the formulation used.
      • Oral testosterone undecanoate, injectable testosterone undecanoate, testosterone-in-adhesive
matrix patch, and testosterone pellets where available.
 
Joint guidelines on the Investigation, Treatment and Monitoring of Late-Onset Hypogonadism in males were published by the International Society for the Study of Aging Male, the International Society of Andrology, the European Association of Urology, the European Academy of Andrology, and the American Society of Andrology in 2009 (Wang, 2009).These guidelines made the following statements:
 
    • The diagnosis of treatable hypogonadism requires the presence of symptoms and signs suggestive of testosterone deficiency (Grade A recommendation; level of evidence 3). The symptom most associated with hypogonadism is low libido (Grade A recommendation; level of evidence 3). Other manifestations of hypogonadism include erectile dysfunction, decreased muscle mass and strength, increased body fat, decreased bone mineral density and osteoporosis, decreased vitality, and depressed mood. None of these symptoms are specific to the low androgen state but may raise suspicion of testosterone deficiency. One or more of these symptoms must be corroborated with a low serum testosterone level (Grade A recommendation; level of evidence 3).
    • Preparations of natural testosterone should be used for substitution therapy. Currently available intramuscular, subdermal, transdermal, oral, and buccal preparations of testosterone are safe and effective (Grade A recommendation; level of evidence 1b). The selection of the preparation should be a joint decision of an informed patient and physician.
 
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Neto and colleagues published a meta-analysis of controlled studies that evaluated the effect of TRT on gains in lean mass (Neto, 2015). This study included 11 trials, 8 of which were included in meta-analysis. The mean change in lean body mass was heterogeneous, with an I2=98%. The combined estimate of mean gain in lean mass was 3.59kg (95% CI 2.38-4.81).
 
A case-control study that was performed within a cohort of 934,283 men aged 45-80 was published (Etminan, 2015). This study identified 30,066 cases of MI, and matched each case with 4 controls. There was no evidence of increased current TRT use in case patients (Relative Risk 1.01, 95% CI 0.89-1.16). There was also no association found between past TRT use and MI, and there was no evidence of different risk according to type of preparation. A small increase in risk was reported for first-time TRT users (1.41, 95% CI 1.06-1.87).
 
A large case-control study was published in 2015 evaluating the risk of VTE associated with TRT (Baillargeon, 2015). This study was performed in 30,572 men age 40 years and older. Cases were individuals with a diagnosis of VTE and prescription for an anticoagulant drug. The cases were each matched with 3 controls on age, time of onset, location, diagnosis of hypogonadism, and presence of a prothrombotic condition. There was no increased risk of TRT in the VTE group (Odds Ratio 0.91, 95% CI 0.38-2.16). The lack of association persisted when different time frames of TRT exposure were examined.
 
Ongoing and Unpublished Clinical Trials
There are a large number of ongoing trials of testosterone replacement therapy. A search of ClinicalTrials.gov in June 2016 using the keywords testosterone replacement, and restricted to intervention trials, returned 130 ongoing trials. Most of these are RCTs in various stages of development. They cover a wide range of potential patient populations, from elderly men with low testosterone levels to more specific populations such as men with prostate cancer. They also cover a wide range of different types of testosterone replacement formulations.
 
2018 Update
A literature search was conducted through August 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
The Endocrine Society commissioned a systematic review and meta-analysis, conducted by Ponce et al, to determine whether testosterone replacement therapy (1) improves sexual function, physical function, fatigue, mood, cognition, anemia, and bone mineral density in men with hypogonadism and (2) is associated with an increased risk of lower urinary tract symptoms and erythrocytosis in men with hypogonadism (Ponce, 2018).  The systematic review evaluated only placebo-controlled randomized trials (4 RCTs; total N=1779 patients) that assigned men with symptomatic hypogonadism with total testosterone level less than 300 ng/dL at screening. Results reported that testosterone replacement therapy was associated with a small but statistically significant improvement in libido, erectile function, sexual activity, and sexual satisfaction compared with placebo but no differences in energy levels or mood. Compared with placebo, testosterone treatment was associated with a significantly higher frequency of erythrocytosis but there was no significant difference in the change in lower urinary tract symptoms. Strengths of this review were inclusion of only RCTs that were low risk of bias, participants who met criteria for the diagnosis of hypogonadism (testosterone level ≤300 ng/dL, and presence of ≥1 symptoms or signs of hypogonadism), and reported outcomes were deemed clinically relevant and important to patients and ascertained using validated instruments. Limitations included the heterogeneity of instruments used to ascertain outcomes across trials, hypogonadism of multiple etiologies and lack of individual patient data meta-analysis to ascertain the relation between symptoms improvement and testosterone levels. Further, none of the trials selected in the systematic review were long enough or large enough to have sufficient statistical power to ascertain safety outcomes (prostate cancer, cardiovascular events, bone fractures).
 
The Endocrine Society has recommended a lower limit for normal levels of 300 ng/dL for total testosterone and 9.0 ng/dL for free testosterone (Bhasin et al [2018]). Joint guidelines from several European and American specialty societies have recommended that replacement therapy be considered at serum total testosterone levels less than 350 ng/dL.
 
In men whose total testosterone is near the lower limit of normal or who have a condition that alters sex hormone-binding globulin, it is recommended that a free T concentration be obtained using either equilibrium dialysis or estimating it using an accurate formula.

CPT/HCPCS:
J1071Injection, testosterone cypionate, 1 mg
J3121Injection, testosterone enanthate, 1 mg
J3145Injection, testosterone undecanoate, 1 mg

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